Process for preparing heterocyclicalkylthioalkyl-N-cyanoguanidines and thioureas

ABSTRACT

Process for preparing heterocyclicalkylthioalkyl-N-cyanoguanidines and thioureas by treating a heterocyclicalkyl derivative with a mercaptoalkyl-N-cyanoguanidine or thiourea. Two specific products are N-cyano-N&#39;-methyl-N&#34;-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine and N-methyl-N&#39;-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea, both useful as histamine H 2  -antagonists.

This is a division of application Ser. No. 606,269 filed Aug. 20, 1975now U.S. Pat. No. 4,013,678.

This invention relates to an improved chemical process. In particular itrelates to an improved process for the production of certainpharmacologically active compounds.

In British Patent No. 1,338,169, thioureas and cyanoguanidines have beendescribed including inter alia compounds of the following formula:##STR1## wherein E is sulphur or NCN, R₁ is hydrogen or lower alkyl suchas methyl, and R₂ is a grouping of the structure shown in Formula II:

        het -- (CH.sub.2).sub.m -- S -- (CH.sub.2).sub.n --                   

FORMULA II

wherein Het is a nitrogen-containing 5 or 6 membered heterocyclic ringsuch as imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole,triazole or thiadiazole which is optionally substituted by lower alkyl,hydroxyl, halogen or amino: and m is 1 or 2, and n is 2 or 3 such thatthe sum of m and n is 3 or 4.

A number of processes for the production of compounds of Formula I werealso described in British Patent No. 1,338,169. In particular there wasdisclosed a process which comprises the reaction of an amine of formulaR₂ NH₂, wherein R₂ has the same significance as in Formula I, with anisothiocyanate of formula R₃ NCS wherein R₃ is lower alkyl or acyl suchas benzoyl to produce compounds of Formula I wherein E is sulphur.

Some disadvantages may be associated with the use of compounds offormula R₃ NCS in a chemical process.

It is an objective of the present invention to provide an alternativeprocess for the production of compounds of Formula I wherein E issulphur, wherein the use of isothiocyanates may be avoided and, as wehave found that the mercapto group of mercaptoalkylthiourea compoundscan be selectively alkylated, this provides the basis for such analternative process. The present invention also relates to analternative process for the production of compounds of Formula I whereinE is NCN.

Accordingly, we provide a process for the production of compounds ofFormula I in which a compound of the following Formula III:

        het -- (CH.sub.2).sub.m -- Z FORMULA III                              

wherein Het and m have the same significance as in Formula II and Z is agroup such that it forms a good leaving group for example halogen,substituted sulphonyloxy such as tosyloxy methanesulphonyloxy ortrifluoromethanesulphonyloxy, substituted benzoyloxy with one or moreelectron-withdrawing substituents such as nitro or chloro,trifluoroacetoxy, or diarylphosphoryloxy, for examplediphenyl-phosphonyloxy, is reacted with a compound of Formula IV:##STR2## wherein n, E and R₁ have the same significance as in Formula I,under basic conditions, for example in the presence of sodium ethoxidein ethanol, in the presence of potassium t-butoxide in t-butanol, orwith sodium hydride in dimethylformamide.

Preferably, Z is chlorine, bromine, methanesulphonyloxy or tosyloxy, andparticularly preferably chlorine. The compounds of Formula III may beprepared from the corresponding alcohols, which are known compounds, bystandard chemical methods; for example, compounds of Formula III whereinZ is chlorine can be prepared from the corresponding alcohol and thionylchloride and compounds of Formula III wherein Z is tosyloxy may beprepared by treating the corresponding alcohol with tosyl chloride inpyridine and, for example in the case of imidazole derivativesselectively removing the N-tosyl group under mild acidic conditions.

The compounds of Formula IV wherein E is NCN may be prepared fromdimethylcyanodithioimidocarbonate by successive reaction with the amineR₁ NH₂ and an amino-alkylmercaptan of formula HS-(CH₂)_(n) -NH₂.

It will be understood that many of the compounds produced and used asstarting materials in the process of our invention may exist in the formof an acid addition salt.

The process of the present invention is particularly advantageous forthe preparation of compounds of Formula I wherein the heterocyclicnucleus may be sensitive to treatment with acids, for example, when theheterocyclic nucleus is oxazole.

The process of the present invention is particularly useful when thecompounds of Formula IV are such that R₁ is methyl or hydrogen.

The process for the production of those compounds of Formula I whereinR₁ is hydrogen and E is sulphur, is particularly advantageous over theprocess described in British Patent Specification No. 1,338,169 sincethe latter process involves a two-step method requiring the use of anacyl isothiocyanate and subsequent hydrolysis of the product.

The process of the present invention is advantageous for the productionof compounds of Formula I wherein R₂ is Het-CH₂ -S-(CH₂)₂ - and isparticularly preferred when Het is imidazole, thiazole, isothiazole orpyridine and is optionally substituted by methyl, chlorine or bromine.Specific compounds which may be made by the present process are thefollowing:

N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea

N-methyl-N'-[2-((5-bromo-4-imidazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((1-methyl-2-imidazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((1-methyl-2-imidazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((2-imidazolyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-((2-thiazolyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-((3-(1,2,4)-triazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea

N-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea

N-methyl-N'-[2-((5-amino-2-(1,3,4)-thiadiazolyl)methylthioethyl]thiourea

N-ethyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea

N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea

N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]guanidine

N-cyano-N'-ethyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((5-bromo-4-imidazolyl)methylthio)-ethyl]guanidine

N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylthio)ethyl]-guanidine

N-cyano-N'-methyl-N"-[2-((3-isothiazolyl)methylthio)ethyl]-guanidine

N-cyano-N'-methyl-N"-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-guanidine.

N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-guanidine

As stated in British Patent No. 1,338,169, the compounds of Formula I(which may be produced by the present process) are pharmacologicallyactive, for example, as histamine H₂ -antagonists (see Nature 1972, 236,385), and they are useful for example, as inhibitors of gastric acidsecretion. For administration they will of course be made up in suitablepharmaceutically acceptable unit dosage forms.

The compounds of Formula I wherein E is sulphur are also useful asintermediates for the production of compounds of Formula I wherein E isNCN, for example,N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea may bereacted with a heavy metal salt of cyanamide such as lead, mercury orcadmium cyanamide to yieldN-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidineor N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea maybe alkylated and the product reacted with cyanamide and a suitablestrong base such as potassium t-butoxide to yieldN-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine.

Throughout this specification by the term "lower alkyl" we refer to analkyl group having from 1 to 4 carbon atoms.

The invention is illustrated but in no way limited by the followingexamples:

EXAMPLE 1

N-Methyl-N¹ -(2-mercaptoethyl)thiourea (3.85 g) in dry ethanol (10 ml)was added to a solution of sodium (1.18 g) in dry ethanol (50 ml) andthe mixture was stirred at room temperature for one hour.4-Chloromethyl-5-methylimidazole hydrochloride (4.29 g) was addedportionwise over one hour to this stirred mixture at room temperature.The mixture was stirred at room temperature for a further hour andheated under reflux for 1/2 hour, cooled and filtered. The filtrate wasevaporated to an oily solid which was recrystallised from water to giveN-methyl-N¹ -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (3.2g) m.p. 149°-151° C.

(Found: C, 44.0: H, 6.6: N, 22.7: S, 25.9: C₉ H₁₆ N₄ S₂ requires: C,44.2: H, 6.6: N, 22.9: S, 26.2%).

EXAMPLE 2

(i) A solution of cysteamine hydrochloride (5.68 g) in water (20 ml) wasadded to a suspension of N-cyano-N,S-dimethylisothiourea (6.46 g) inethanol (100 ml). A solution of sodium hydroxide (4.0 g) in water (20ml) was added to the mixture and the suspension was heated under refluxfor one hour. The resulting clear solution was concentrated to removeethanol, a little more water was added and the alkaline aqueous solutionwas extracted with ethyl acetate. The aqueous solution was adjusted topH4 with hydrochloric acid and extracted with ethyl acetate. This latterorganic extract was dried and evaporated to giveN-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.12 g) as a colourlessoil.

In order to characterise this product a solution of2,4-dinitrochlorobenzene (7.7 g) in 95% ethanol (50 ml) was added to asolution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.0 g) in95% ethanol. The mixture was refluxed for one hour and cooled. Theresulting crystalline solid (7.73 g) was collected and was trituratedwith a large volume of ether and was recrystallised from acetonitrile toaffordN-cyano-N'-methyl-N"-[S-(2,4-dinitrophenyl)-2-mercaptoethyl]-guanidine,m.p. 210°-211° C.

Found: C, 41.0: H, 3.7: N, 26.0: S, 10.0: C₁₁ H₁₂ N₆ O₄ S requires: C,40.7: H, 3.7: N, 25.9: S, 9.9%).

(ii) Sodium (1.43 g) was added, with stirring under nitrogen, to dryethanol (100 ml). After the sodium had dissolved a solution ofN-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (4.90 g) in dry ethanol(50 ml) was added and the mixture was stirred at room temperature forone hour. 5-Methyl-4-chloromethylimidazole hydrochloride (5.18 g) wasadded in batches over a period of 1 hour at room temperature. Themixture was then stirred at room temperature, for a further hour andheated at reflux temperature for 1/2 hour. After cooling the mixture wasfiltered and the filtrate was evaporated to a glassy solid (8.8 g). Thiscrude product was chromatographed on silica gel with acetonitrile aseluant and the solid product obtained (3.60 g) was recrystallised fromacetonitrile to giveN-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine,m.p. = 140°-142° C.

(Found: C, 47.9: H, 6.3: N, 33.3: S, 12.5: C₁₀ H₁₆ N₆ S requires: C,47.6: H, 6.4: N, 33.3: S, 12.7%)

EXAMPLE 3

Substitution of

(a) N-(2-mercaptoethyl)thiourea

(b) N-ethyl-N'-(2-mercaptoethyl)thiourea

(c) N-butyl-N'-(2-mercaptoethyl)thiourea

(d) N-methyl-N'-(2-mercaptopropyl)thiourea

for N-methyl-N'-(2-mercaptoethyl)thiourea in the procedure of Example 1leads to the production of

(a) N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea

(b) N-ethyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea

(c) N-butyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea

(d) N-methyl-N'-[3-((5-methyl-4-imidazolyl)methylthio)propyl]thiourea

The starting materials may be prepared by published methods (see J. Org.Chem. 28, 3140 (1963) and 33, 884 (1968)), and methods directlyanalogous to published methods.

EXAMPLE 4

Substitution of

(a) N-cyano-N'-(2-mercaptoethyl)guanidine

(b) N-cyano-N'-ethyl-N"-(2-mercaptoethyl)guanidine

(c) N-cyano-N'-butyl-N"-(2-mercaptoethyl)guanidine

(d) N-cyano-N'-methyl-N"-(3-mercaptopropyl)guanidine

for N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine in the procedure ofExample 2(ii) leads to the production of (a)

(a) N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]guanidine

(b)N-cyano-N'-ethyl-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine

(c)N-cyano-N'-butyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine

(d)N-cyano-N'-methyl-N"-[3-((5-methyl-4-imidazolyl)methylthio)propyl]guanidine

The starting materials may be prepared by successively treating N-cyanodimethyldithioimidocarbonate with ammonia, methylamine, ethylamine orbutylamine, and 2-mercaptoethylamine or 3-mercaptopropylamine.

EXAMPLE 5

Substitution of

(a) 4-(chloromethyl)imidazole

(b) 4-(chloromethyl)-5-bromoimidazole

(c) 2-(chloromethyl)-1-methylimidazole

(d) 2-(chloromethyl)imidazole

(e) 2-(chloromethyl)thiazole

(f) 3-(chloromethyl)-(1,2,4)triazole

(g) 3-(chloromethyl)isothiazole

(h) 3-(chloromethyl)isoxazole

(i) 2-(chloromethyl)-5-amino-(1,3,4)thiadiazole

(j) 2-(chloromethyl)-3-methylpyridine

(k) 2-(chloromethyl)-3-chloropyridine

(l) 2-(chloromethyl)-3-bromopyridine

(m) 2-(chloromethyl)-3-hydroxypyridine

(n) 4-(2-chloroethyl)imidazole

for 4-chloromethyl-5-methylimidazole in the procedure of Example 1 leadsto the production of

(a) N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea

(b) N-methyl-N'-[2-((5-bromo-4-imidazolyl)methylthio)-ethyl]thiourea

(c) N-methyl-N'-[2-((1-methyl-2-imidazolyl)methylthio)-ethyl]thiourea

(d) N-methyl-N'-[2-((2-imidazolyl)methylthio)ethyl]-thiourea

(e) N-methyl-N'-[2-((2-thiazolyl)methylthio)ethyl]thiourea

(f) N-methyl-N'-[2-((3-(1,2,4)-triazolyl)methylthio)ethyl]thiourea

(g) N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea

(h) N-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea

(i)N-methyl-N'-[2-((5-amino-2-(1,3,4)-thiadiazolyl)-methylthioethyl]thiourea

(j) N-methyl-N'-[2-((3-methyl-2-pyridyl)methylthio)-ethyl]thiourea

(k) N-methyl-N'-[2-((3-chloro-2-pyridyl)methylthio)-ethyl]thiourea

(l) N-methyl-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-thiourea

(m) N-methyl-N'-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]thiourea

(n) N-methyl-N'-[2-(4-imidazolylethylthio)ethyl]thiourea

The starting materials are either known compounds or may be preparedfrom the corresponding hydroxymethyl derivatives by standard methodse.g., treatment with thionyl chloride or from alkoxymethyl derivativesby ether cleavage e.g., with hydrobromic acid and treatment of theproduct with thionyl chloride.

EXAMPLE 6

Substitution of

(a) 4-(chloromethyl)imidazole

(b) 4-(chloromethyl)-5-bromoimidazole

(c) 2-(chloromethyl)-1-methylimidazole

(d) 2-(chloromethyl)imidazole

(e) 2-(chloromethyl)thiazole

(f) 3-(chloromethyl)-(1,2,4)triazole

(g) 3-(chloromethyl)isothiazole

(h) 3-(chloromethyl)isoxazole

(i) 2-(chloromethyl)-5-amino-(1,3,4)thiadiazole

(j) 2-(chloromethyl)-3-methylpyridine

(k) 2-(chloromethyl)-3-chloropyridine

(l) 2-(chloromethyl)-3-bromopyridine

(m) 2-(chloromethyl)-3-hydroxypyridine

(n) 4-(2-chloroethyl)imidazole

for 4-chloromethyl-5-methylimidazole in the procedure of Example 2(ii)leads to the production of

(a) N-cyano-N'-methyl-N"-[2-(4-imidazolylmethylthio)-ethyl]guanidine

(b)N-cyano-N'-methyl-N"-[2-((5-bromo-4-imidazolyl)-methylthio)ethyl]guanidine

(c)N-cyano-N'-methyl-N"-[2-((1-methyl-2-imidazolyl)-methylthio)ethyl]guanidine

(d) N-cyano-N'-methyl-N"-[2-((2-imidazolyl)methylthio)-ethyl]guanidine

(e) N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylthio)-ethyl]guanidine

(f)N-cyano-N'-methyl-N"-[2-((3-(1,2,4)-triazolyl)-methylthio)ethyl]guanidine

(g) N-cyano-N'-methyl-N"-[2-(3-isothiazolylmethylthio)-ethyl]guanidine

(h) N-cyano-N'-methyl-N"-[2-(3-isoxazolylmethylthio)-ethyl]guanidine

(i)N-cyano-N'-methyl-N"-[2-((5-amino-2-(1,3,4)-thiadiazolyl)methylthio)ethyl]guanidine

(j)N-cyano-N'-methyl-N"-[2-((3-methyl-2-pyridyl)-methylthio)ethyl]guanidine

(k)N-cyano-N'-methyl-N"-[2-((3-chloro-2-pyridyl)-methylthio)ethyl]guanidine

(l)N-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]guanidine

(m) N-cyano-N'-methyl-N"-[2-(4-imidazolylethylthio)-ethyl]guanidine

EXAMPLE 7

Substitution of 2-(chloromethyl)oxazole for4-chloromethyl-5-methylimidazole in the procedure of Example 1 and theprocedure of Example 2(ii) leads to the production ofN-methyl-N'-[2-(2-oxazolylmethylthio)ethyl]-thiourea andN-cyano-N'-methyl-N"-[2-(2-oxazolylmethylthio)ethyl]guanidinerespectively.

EXAMPLE 8

Treatment of 2-pyridinemethanol under basic conditions with

(a) p-toluenesulphonic anhydride

(b) p-nitrobenzoyl chloride

(c) p-chlorobenzoyl chloride

(d) trifluoromethanesulphonyl chloride

(e) methanesulphonyl chloride

(f) diphenylphosphoryl chloride leads to the production of:

(a) 2-pyridylmethyl p-toluenesulphonate

(b) 2-pyridylmethyl p-nitrobenzoate

(c) 2-pyridylmethyl p-chlorobenzoate

(d) 2-pyridylmethyl trifluoromethylsulphonate

(e) 2-pyridylmethyl methanesulphonate

(f) 2-pyridylmethyl diphenylphosphinate and the treatment of theseproducts with N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine and sodiumethoxide in ethanol leads to the production ofN-cyano-N'-methyl-N"-[2-(2-pyridylmethylthio)ethyl]guanidine.

EXAMPLE 9

Treatment of 2-bromomethyl pyridine withN-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine and sodium ethoxide inethanol leads to the production ofN-cyano-N'-methyl-N"-[2-(2-pyridylmethylthio)ethyl]guanidine.

What we claim is:
 1. A process for the production of a compound of theformula: ##STR3## wherein E is sulphur or NCN, R₁ is hydrogen or loweralkyl, and R₂ is a grouping of the structure

        Het -- (CH.sub.2).sub.m -- S -- (CH.sub.2).sub.n --                   

wherein Het is a nitrogen containing 5 or 6 membered heterocyclic ringselected from imidazole, pyridine, thiazole, isothiazole, oxazole,triazole or thiadiazole which ring is optionally substituted by loweralkyl, hydroxyl, halogen or amino; and m is 1 or 2, and n is 2 or 3 suchthat the sum of m and n is 3 or 4; which comprises treating a compoundof the formula

        Het -- (CH.sub.2).sub.m -- Z                                          

wherein Het and m are as defined hereinabove and Z is a group selectedfrom tosyloxy, methanesulphonyloxy, trifluoromethanesulphonyloxy,benzoyloxy with one or more nitro or chloro substituents,trifluoroacetoxy or diphenylphosphoryloxy, which forms a good leavinggroup, with a mercaptan of the formula ##STR4## wherein n, E and R₁ areas defined hereinabove, in the presence of a base, said reactants andbase being present in molar equivalent amounts.
 2. A process accordingto claim 1 wherein Z is methanesulphonyloxy or tosyloxy.
 3. A processaccording to claim 1 wherein Het is an imidazole, thiazole, isothiazoleor pyridine ring optionally substituted by methyl, chlorine or bromine.4. A process according to claim 1 wherein m is 1 and n is
 2. 5. Aprocess according to claim 1 wherein R₁ is methyl.
 6. A processaccording to claim 1 wherein R₁ is hydrogen and E is sulphur.
 7. Aprocess according to claim 1 wherein R₁ is methyl, Het is5-methyl-4-imidazolyl, m is 1 and n is
 2. 8. A process according toclaim 7 wherein E in NCN.